An SPP1-SOCS1 pathway constrains interferon responses in tumor-associated macrophages and shapes an immunosuppressive tumor microenvironment.

Tumor-associated macrophages (TAMs) can suppress antitumor immunity and reduce responses to immune checkpoint blockade (ICB). Here, we asked how TAM programs contribute to ICB non-response. Integration of public single-cell RNA sequencing (scRNA-seq) datasets across 12 cancer types identified SPP1+ TAMs as a tumor-enriched macrophage subset with immunosuppressive features. TAMs from ICB non-responders across multiple tumor types exhibited higher SPP1 expression. In murine models, macrophage Spp1 deletion suppressed tumor growth and prolonged survival and was associated with a remodeled tumor microenvironment featuring reduced T regulatory cell (Treg) frequencies, increased interferon (IFN)-γ+ CD4+ and GZMB+ CD8+ T cells, and augmented interferon-stimulated gene (ISG) expression across immune and malignant compartments. Mechanistically, intracellular SPP1 interacted with TRIM21 to limit SOCS1 ubiquitination, stabilizing SOCS1-mediated negative feedback and dampening IFN-γ-STAT1-ISG signaling in TAMs. Consistently, SPP1 targeting enhanced the efficacy of anti-PD-L1 therapy in vivo. Thus, remodeling the TME via targeting the TAM SPP1-IFN-γ axis presents a therapeutic avenue for enhancing responses to ICB.